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    • Bile acids BAs are critical for facilitating

    2022-06-24

    Bile acids (BAs) are critical for facilitating the Necrostatin 2 of dietary lipids and lipid-soluble vitamins in the intestines [6], [7]. At physiological levels, BAs function as signaling molecules and activate specific nuclear receptors [farnesoid X receptor (FXR), pregnane X receptor, and vitamin D receptor] [8], [9], [10], [11], [12], [13] and membrane receptors [G protein-coupled bile acid receptor 1 (TGR5) and sphingosine-1 phosphate receptor 2 [14], [15]. Specifically, FXR is a ligand-activated transcription factor belonging to the nuclear receptor superfamily, and is essential for regulating BA and lipid homeostasis. FXR has been shown to suppress liver steatosis [16], [17], [18], [19], inflammation and fibrosis [20], [21], thus playing a critical role in the prevention and treatment of the nonalcoholic steatohepatitis [18], [19], [21]. FXR has also been shown to promote liver regeneration [22], and therefore, enhances recovery from chemical-induced liver injury or liver resection. Previous studies suggest alcohol may down-regulate the expression and function of FXR [23], [24], which may be responsible for altered BA synthesis and total BA pool size. Deficiency of FXR is unable to suppress BA synthesis by FXR-mediated negative feedback mechanisms, and thereby increases BA levels in the body [6]. Therefore, high concentrations of BAs can damage cells, induce apoptosis, and promote tumorigenesis [7], [25]. FXR has previously been shown to protect the liver from chronic alcohol-induced injury and cellular damage, as activation of FXR by synthetic agonists WAY-362450 or obeticholic acid attenuated chronic alcohol-induced liver injury, steatosis, and oxidative stress [23], [24]. However, the mechanisms are not clear. Current evidence suggests that activation of intestinal FXR protects against ethanol-induced liver disease by inhibiting BA synthesis and reducing BA toxicity in the liver [26]. Moreover, FXR is involved in maintaining and preserving the integrity and function of the intestinal barrier, and preventing bacterial translocation from the intestinal tract [27], [28]. Ethanol exposure has been shown to induce bacterial translocation and increase gut permeability, which promotes endotoxemia and the development of ALD [29]. In agreement with the importance of intestinal FXR to mitigate ALD, our previous study found that hepatic FXR plays only a minor role in ameliorating ethanol-induced injury, therefore FXR in extra-hepatic tissues may be responsible for effects on ALD development [30]. In this study we used whole-body FXR knockout mice (FXR−/−) and a chronic-plus-binge ethanol feeding model to study the effects of whole-body FXR deficiency on BA metabolism in ALD development.
    Materials and methods
    Results
    Discussion ALD presents as a spectrum of varying severities of liver pathology, ranging from simple steatosis, inflammation with hepatocyte ballooning, variable grades of fibrosis, to cirrhosis [1]. In this study, we have shown that ethanol induced more severe liver injury in FXR−/− mice than in WT mice, revealed by lipid accumulation, hepatocyte ballooning, and increased serum ALT levels. However, after ethanol feeding, FXR−/− mice only showed a slight increase in the hepatic expression of a pro-inflammatory cytokine, Tnfα, increased basal expression of acute phase protein, Lcn2, but no significant disturbance of NF-κB signaling pathway. FXR deficiency led to increased lipid peroxidation in the liver, suggesting increased oxidative stress following ethanol-feeding. Therefore, lipid accumulation might be the major cause for liver injury in this chronic-binge ethanol feeding model. As an essential nuclear receptor regulating BA homeostasis [7], [18], FXR is generally thought to be suppressed by ethanol, and thus resulting in increased BA synthesis, BA levels, liver injury, and inflammation during ALD [26]. However, not all BAs are toxic. Previous reports suggest that BA toxicity to the liver is related to the hydrophobicity of the individual BA specie, with hydrophobic BA species being more cytotoxic and hydrophilic BA species being less toxic. Emerging evidence suggests that TCA contributes to endoplasmic reticulum stress and thus induces liver damage mediated by JNK pathway [33]. In this study, ethanol exposure increased TCA levels in WT mice, and to a greater extent, in FXR−/− mice. However, no relationship between ethanol-induced liver injury and increased JNK signaling in FXR−/− mice after chronic-ethanol feeding was observed in this study. The downstream transcription factor, cJun, in the JNK pathway was induced in WT and FXR−/− mice by ethanol, indicating that JNK pathway might be involved in the ethanol-induced liver injury. Moreover, our previous study showed that deletion of FXR in hepatocytes only did not worsen liver injury under chronic-binge ethanol feeding [30]. These combined data suggest a greater role of intestinal FXR signaling in the protection against ethanol-induced liver injury.